Nat. Med., published online 29 July 2012; doi: 10.1038/nm.2851

Credit: SAMIR BHATTACHARYA

Insulin sensitivity is compromised by an overproduction of proinflammatory cytokines from adipose tissue that has been stimulated by free fatty acids (FFAs). This insulin resistance is mediated through TLR4, a receptor that signals through NF-kB and is involved in innate immunity. However, FFAs do not directly interact with TLR4, so how they activate signaling downstream of the receptor is unclear. Fetuin-A (FetA), a glycoprotein secreted from the liver, is known to be upregulated by FFAs and stimulate production of inflammatory cytokines from adipocytes. Also, FetA knockout mice are protected from insulin resistance triggered by a high-fat diet. Given these clues, Pal et al. predicted that FetA could be an endogenous ligand for TLR4. In a first test of this theory, the authors found that serum FetA, TLR4 expression and NF-kB activation were each increased in adipocytes of obese diabetic subjects and insulin-resistant and dislipidemic mice. Similarities between fetA and tlr4 knockdowns indicated that association among FFAs, FetA and TLR4 are most likely linked to lipid-mediated insulin resistance. Indeed, they found that FetA is required for FFA-induced TLR4 signaling. FFAs bound FetA in a lipid-protein overlay assay, by coimmunoprecipitation and in a yeast two-hybrid system. The FetA-TLR4 interaction is of very high affinity as shown by surface plasmon resonance. Finally, mutations that diminish the FetA-TLR4 interaction failed to produce FFA-induced insulin resistance. A ternary FFA–FetA–TLR4 complex therefore mediates lipid-mediated insulin resistance.